Nicotinic ACh receptors (nAChRs) comprise a class of pentameric (containing five subunits) ligand-gated ion channels present in the central (CNS) and the peripheral (PNS) nervous systems as well as in the striated muscle. The nAChR of the nervous system and those found in peripheral neurons differ in structural (subunits composition) and functional aspects from nAChR found in striated muscles. Whereas the striated muscle receptors contain 2 α subunits (α1) and one β (β1), one γ and one δ (or one ε) subunits, the neuronal nAChR is composed of only α (at least two subunits among the α2 to α10 subtypes) and β (generally three subunits among the β 2 to β 4 subtypes). The amino acid sequence for the α subunits of the neuronal nAChR (α2 to α10) consists of a glycolipid region (which contains the ACh binding site and four hydrophobic regions that span the membrane. The neuronal β subunits (β 2 to β 4) do not have an adjacent pair of cystines, which are present in the α subunit ligand-binding region.
In general terms, two molecules of ACh binds to each of the α-subunits of the receptor and induce a conformational change in all the receptor subunits, resulting in an opening of Na+/K+ channel, causing a local depolarization. The local depolarization may develop to an action potential, leading to physiological response such as muscle contraction when summed with the action of several receptors in the neuromuscular junction. Nicotinic receptors possess a relatively low affinity for ACh at rest. The affinity for acetylcholine is increased after the binding of the first ACh molecule (through an allosteric mechanism, which increases the likelihood of another molecule of ACh binding to the other α subunit). After prolonged exposure to ACh and at e.g., high concentrations of this neurotransmitter, the receptor channel may be closed in spite of an e.g., increase affinity of ACh to the receptor and the receptor subsequently can become desensitized.
An allosteric transition state model of the nAChR involves at least a resting state, an activated state and a “desensitized” closed channel state. Different nAChR ligands can differentially stabilize the conformational state to which they preferentially bind. For example, the agonists ACh and (−)-nicotine stabilize first the active state and then the desensitized state.
The nAChR is involved in the regulation of a variety of brain functions such as thermoregulation, cognition, attention etc. Thus, potentially, treatment with nicotine or drugs that directly or indirectly activate the nAChR may provide beneficial effects in alleviating cognitive dysfunctions such as dementia of Alzheimer's type, cognitive impairment associated with schizophrenia, attention deficit, e.g., in attention deficit hyperactivity disorder (ADHD). Nicotine has also been shown to be neuroprotective and a negative correlation between smoking and the development of neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease has also been reported. In addition, nicotine is also used in cessation of smoking.
Over the past several years, a variety of research groups have focused on the development of selective nicotinic agonists. Nicotinic agonists may be useful in the treatment of a variety of neurological disorders including Alzheimer's disease, Parkinson's disease, and chronic pain. For example, nicotinic agonists such as epibatidine, epiboxidine, ABT-418, ABT-594, and SIB-1508 (altinicline) have been shown to exhibit analgesic properties suggesting that nAChR may be used as targets for novel analgesics.
The rapid desensitization of the nAChR may make nicotine, and other agents that activate directly or indirectly the nicotinic receptors, ineffective as therapeutic drugs. In addition, nicotinic agonists may be ineffective due to a process of uncompetitive blockade (open-channel block). Furthermore, prolonged activation appears to induce a long-lasting receptor inactivation. It would be desirable to find drugs that would retard desensitization of the receptor, thus prolonging the positive effect of nicotinic agonists or making them more effective during repeated administration.